Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those mediating alcohol-induced neuronal injury. During the previous period of funding, we demonstrated alcohol-induced impairment of the blood brain barrier (BBB) and neuronal injury and delineated molecular mechanisms of these previously unrecognized phenomena. We showed that alcohol exposure increased neuroinflammation in an animal model of HIV-1 encephalitis (HIVE), confirming that alcohol abuse is an exacerbating factor in HIV-1 brain infection. Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-1 and alcohol mediated neurodegeneration. Agonists of cannabinoid receptor 2 (CB2) possess potent anti-inflammatory and neuroprotective properties. We propose that CB2 activation will attenuate neuronal dysfunction and BBB injury caused by alcohol and HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Relevance of this idea is confirmed by our findings of augmented CB2 expression on brain endothelium in alcoholics, HIVE patients and up-regulated CB2 expression in primary human brain microvascular endothelial cells (BMVEC) by alcohol and cytokines. CB2 agonists protected the barrier against inflammatory and alcohol insults, blocked monocyte migration across BBB and decreased expression of pro-inflammatory factors in activated BMVEC. CB2 agonist decreased leukocyte adhesion to brain endothelium and prevented enhanced BBB permeability in mice with systemic inflammation. Based on these observations, we propose to investigate the therapeutic potential of CB2 activation in diminution of neuroinflammation caused by the combined effects of alcohol and HIV-1. The following questions will be addressed: 1) How do CB2 agonists reverse the effects of alcohol and virus infection on BBB integrity and diminish migration of HIV-1-infected monocytes across the BBB, 2) Can CB2 stimulation ameliorate alcohol and HIV-1-infected macrophage-mediated neurotoxicity, and 3) Can CB2 agonists diminish neuroinflammation, neuronal injury, and BBB dysfunction in an animal model of HIVE and alcohol abuse. The significance of the proposed work is to uncover novel mechanisms underlying the anti-inflammatory potential of CB2 activation that will ameliorate BBB impairment and neuronal dysfunction in the setting of HIV-1 CNS infection and alcohol abuse. PUBLIC HEALTH RELEVANCE: According to the 2001-2 National Epidemiologic Survey on Alcohol and Related Conditions Survey, more than 20% of men (age 18 to 29) met the criteria for a diagnosable alcohol use disorder: 9.3% Alcohol Abuse and 13% Alcohol Dependence. Clinical studies indicated that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. The current proposal aims to understand mechanisms of the combined effects of HIV-1 and alcohol abuse in the brain and to propose neuroprotective therapies.